Antibody derivatives with multiple Fc fragments have a variety of therapeutic applications, especially when the Fc fragments are linked to Fab fragments or functionally similar moieties to form combinations having "chimeric" properties. When chimeric antibodies are used as immunotherapeutic agents, the Fc fragments used to make the intermediates should be derived from the same species as the intended recipient to minimize antigenicity and maximize recruitment of natural effectors. Thus, human Fc fragments are preferred for making chimeric antibodies that are intended for use as immunotherapeutic agents in humans.
Chimeric antibodies in which the Fc fragments are derived from normal human IgG and the Fab fragments are derived from xenogeneic antibody (usually mouse monoclonal IgG) maximize cytotoxicity mediated via recruitment of natural effectors. The preparation of chimeric antibodies in which the antigen binding (Fab) arms of rodent IgG antibody are chemically linked by thioether bonds to human IgG, or to the Fc-gamma portion of human IgG, has been reported in Stevenson et al., "Surface Immunoglobulin of B-lymphocytic Tumours as a Therapeutic Target," Cancer Surveys, 4:213 (1985). A chemically synthesized FabFc chimera was prepared in quantity from monoclonal anti-Id and used in the treatment of human lymphoma as described in Hamblin et al., Blood, 42:495 (1987).
This chemically-derived FabFc chimera exhibited the advantages expected from displaying human instead of rodent Fc-gamma of better recruitment of effectors (complement and various cells displaying Fc-gamma receptors), a longer metabolic survival and a lower immunogenicity. A comprehensive review of work in this field is contained in Cancer Surveys, Vol. 4 No. 1 (1985) (Stevenson and Glennie).
It has been reported that cooperative binding between Fc-gamma and the host's natural effector molecules are enhanced by having two Fc-gamma fragments on each synthetic antibody molecule. Synthetic antibodies having multiple Fc fragments have been constructed by chemically joining two synthetic chimeric antibodies, each having a mouse Fab-gamma fragment linked via a thioether bond [--S--R--S--] to a human Fc-gamma fragment. The two chimeric antibodies are joined via a thioether bond between their two respective Fc-gamma fragments to form bisFab--Fc [FabFc--S--R--S--FcFab]. Stevenson, et al., "A Chimeric Antibody with Dual Fc Regions (bisFabFc) Prepared by Manipulations at the IgG Hinge," Anti-Cancer Drug Design, 3:219-230 (1989) and Stevenson, "Attack on Neoplastic Cell Membranes by Therapeutic Antibody," Molecular and Cellular Biochemistry, 91:33-38 (1989).